Cutaneous T-cell lymphoma (CTCL) is a clonally-derived, skin-invasive malignancy of CD4+ T-lymphocytes with the phenotype of mature helper T-cells. Patients with advanced forms of CTCL characterized by multiple tumors or peripheral blood involvement typically have a poor prognosis. Our previous work has demonstrated that advanced CTCL is characterized by prominent immunologic defects including depressed cell-mediated immunity. A marked defect in IL-12 production in CTCL has also been noted, which may play a role in depressed cell-mediated immunity. Because evidence exists for an antitumor T-cell response and since IL-12 is pivotal in stimulating cytotoxic T-cells, our IL- 12 multicenter trial group has completed a small phase I dose escalation trial of IL-12 with 5 of 9 evaluable patients responding and a phase II single dose trial with 10 of 23 evaluable patients responding. Key observations in these small studies were 1)responses were rapid but were often eventually associated with an IL-12 refractory state 2) the latter may be associated with down modulation of IL-12 receptors on lymphocytes 3) regressing lesions were intensely infiltrated with cytotoxic T-cells and 4) more robust responses occurred at the lower dose of 100 ng/kg used in the phase I trial. This proposal plans another multicenter phase II IL-12 trial using 100 ng/kg sub Q twice weekly for 24 weeks and, because of in vitro synergism with IL-12, adds IL-2 in differing doses at week 13 for all but those with progressive disease. We also propose to investigate the in vivo mechanisms of action of IL-12 by studying 1) skin infiltrating immune cells, 2) cytokine production in situ in skin lesions, and 3) extent of apoptosis within active skin lesions prior to and during IL-12 therapy and correlate this with lesion regression. We will also examine IL-12 responsive NK cell activity and interferon gamma production in concert with IL-12 receptor expression and IL-12 signal transduction prior to and prospectively during therapy to determine if downmodulation of receptors or alteration of Jak-Stat pathways accounts for tolerance to the clinical effects of IL-12. The results of these studies will further improve our understanding of the mechanisms of action of IL-12 and will assist in targeting a more effective dose of IL-12 for CTCL. Moreover, the addition of low-dose IL-2 may yield a more efficacious combination of agents which may synergistically enhance anti-tumor immunity and clinical responses.